title: Comparative profiling of primary colorectal carcinomas and liver metastases identifies LEF1 as a prognostic biomarker.
abstract: OBJECTIVE
  We sought to identify genes of clinical significance to predict survival and the risk for colorectal liver metastasis (CLM), the most common site of metastasis from colorectal cancer (CRC).
  
  
  METHODS
  We profiled gene expression in 31 specimens from primary CRC and 32 unmatched specimens of CLM, and performed Significance Analysis of Microarrays (SAM) to identify genes differentially expressed between these two groups. To characterize the clinical relevance of two highly-ranked differentially-expressed genes, we analyzed the expression of secreted phosphoprotein 1 (SPP1 or osteopontin) and lymphoid enhancer factor-1 (LEF1) by immunohistochemistry using a tissue microarray (TMA) representing an independent set of 154 patients with primary CRC.
  
  
  RESULTS
  Supervised analysis using SAM identified 963 genes with significantly higher expression in CLM compared to primary CRC, with a false discovery rate of <0.5%. TMA analysis showed SPP1 and LEF1 protein overexpression in 60% and 44% of CRC cases, respectively. Subsequent occurrence of CLM was significantly correlated with the overexpression of LEF1 (chi-square p = 0.042), but not SPP1 (p = 0.14). Kaplan Meier analysis revealed significantly worse survival in patients with overexpression of LEF1 (p<0.01), but not SPP1 (p = 0.11). Both univariate and multivariate analyses identified stage (p<0.0001) and LEF1 overexpression (p<0.05) as important prognostic markers, but not tumor grade or SPP1.
  
  
  CONCLUSIONS
  Among genes differentially expressed between CLM and primary CRC, we demonstrate overexpression of LEF1 in primary CRC to be a prognostic factor for poor survival and increased risk for liver metastasis.
authors.affiliation: Department of Medicine, Santa Clara Valley Medical Center, San Jose, California, United States of America. albert.lin@hhs.sccgov.org
authors.forename: Albert Y
authors.initials: AY
authors.lastname: Lin
authors.forename: Mei-Sze
authors.initials: MS
authors.lastname: Chua
authors.forename: Yoon-La
authors.initials: YL
authors.lastname: Choi
authors.forename: William
authors.initials: W
authors.lastname: Yeh
authors.forename: Young H
authors.initials: YH
authors.lastname: Kim
authors.forename: Raymond
authors.initials: R
authors.lastname: Azzi
authors.forename: Gregg A
authors.initials: GA
authors.lastname: Adams
authors.forename: Kristin
authors.initials: K
authors.lastname: Sainani
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.forename: Samuel K
authors.initials: SK
authors.lastname: So
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Pollack
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology; D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000556:secondary*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis / Q000378:metabolism; D011379:Prognosis; D016019:Survival Analysis; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D009363:Neoplasm Proteins